Animals have evolved intricate
chemical strategies for obtaining
food and for defending themselves
against infection, disease, and
predation. It seems only natural that
those chemical compounds could
have broader healing properties.
In fact, the animal kingdom is like
a drugstore, offering thousands
of fascinating compounds, many
of which can help heal humans in
unexpected ways.

Leeches are back—scientists have
found new medical
uses for these and
other animals. (Premaphotos/ naturepl.com)

In 19th century European medicine, leeches
were often prescribed as a treatment for
headaches, fever, obesity, and many other
maladies. We’ve since scoffed at how people
considered bleeding-by-leech as a cure-all, but
there’s no need to throw the leeches out with
the bathwater.

Leeches, it turns out, have some valuable
medicinal uses in the 21st century. These
FDA-approved invertebrates are used in
hospitals to improve the outcome of surgeries
to reattach fingers, toes, flaps of skin, and
other small body parts.

Surgeons use leeches to drain blood from a
swollen area without damaging tissue as a needle
would. The leech’s saliva contains anesthetic
compounds so there is no pain. Perhaps more
importantly, the saliva contains anticoagulating
compounds that keep the wound slowly but
steadily bleeding for hours.

While leeches are already in widespread use
as postsurgical treatment, anticoagulating and
anti-inflammatory compounds in their saliva are
being studied as potential ingredients for drugs
to treat congestive heart failure, strokes, and
perhaps even arthritis. Scientists are working
to isolate and identify as many compounds as
they can from leeches all over the world, some
species of which are endangered.

The leech is just one example of an animal
that helps humans heal. Many prescription
drugs were inspired by animals. The blood
pressure drug Captopril is modeled on a
peptide in the venom of the Brazilian viper.
The leukemia drug cytarabine is based on
compounds from a Caribbean sponge. And
many more possibilities are under development.
Scorpion venom is being tested as a treatment
for brain tumors, and a compound from the
internal organs of sharks has shown promise
in treating ovarian cancer, prostate cancer, and
macular degeneration.

From bees to frogs, members of the animal
kingdom have the potential to offer a surprising
range of medical help to humans.

Sweet Healing from Bees

The ancient Egyptians used to spread honey on
wounds to speed healing. Four thousand years
later, Jennifer Eddy does the same thing.

Eddy, assistant professor of family medicine at
the University of Wisconsin School of Medicine
and Public Health, first used honey several years
ago as a last resort. Her patient, a 79-year-old
man with type 2 diabetes, had large open ulcers
on his feet that were continuing to worsen
despite standard medical treatment. Nonhealing
foot ulcers are a common and serious problem
for diabetics, who have reduced sensation and
poor blood circulation in their feet. The ulcers
often require amputation of a toe, foot, or leg to
stop the spread of infection. “Nothing we tried
medically was working,” Eddy says. “He refused
amputation and he was going home to die.”

Meanwhile, Eddy left for a honeymoon trip,
where she happened to read a book about folk
remedies. It mentioned using honey to treat
wounds. Eddy remembered another book, The
Healing Hand, written by one of her pathology
professors, that described ancient Egyptians
using honey the same way.

When she returned to
work, she found reports in the medical literature
supporting the healing powers of honey. Her
patient agreed to give it a try. He stopped taking
antibiotics, and once a day his wife spread a thick
layer of supermarket honey on gauze squares that
she taped on his wounds. To everyone’s delight,
the wounds improved quickly and, after several
months, healed completely.

In the last few years, more scientific studies
have backed up honey’s benefits, and, in 2007,
the FDA approved several medical-grade
honeys for use in treating wounds.
Honey attacks microbes on at least three
levels, according to Eddy. First of all, honey has
very low water content. “If you put it next to
something that has water in it, like bacteria or
a wound, it will suck the water out of it,” Eddy
says. “So it dehydrates bacteria.” Second, it’s
acidic, which wound-dwelling bacteria don’t
like. (A drawback of honey therapy is that
it may sting after application.) Third, honey
contains an enzyme that leads to the production
of hydrogen peroxide, which kills bacteria.
Because honey kills microbes several ways,
microbes have a hard time evolving resistance to it.
Some studies show that honey helps uninfected
wounds heal faster, too. Eddy says that’s because
honey acts like a moist bandage that allows new
skin cells to form around the edges of the wound.
It also pulls water from the wound, reducing
swelling and improving blood supply.

So why do bees need antimicrobial honey?
There seems to be a logical explanation:
Honey is their main food source, and it’s all
they have to eat over the winter. If it were to
get moldy or infested with bacteria, the entire
hive could starve.

Today, Eddy is running a pilot study in the
clinic at her university hospital to rigorously
evaluate honey’s effectiveness in treating diabetic
foot ulcers. Half of the patients are receiving the
honey treatment, and half are being treated with
a placebo that looks and smells like the real thing.
Neither the patients nor the doctors will know
which is which until all the wounds have been
evaluated for healing. Eddy expects the results of
the study to be available in about a year.
While there is evidence that honey helps
other kinds of wounds heal, Eddy is focusing
on diabetic foot ulcers because of their cost to
diabetics and to society. People with diabetic
foot ulcers typically receive multiple courses
of antibiotics, leading to the development of
antibiotic-resistant bacteria. “Having a nonhealing
wound helps grow those bad bugs,” she
says. “Diabetic foot ulcers are a societal repository
for some of the most resistant bacteria.”

The Secret First Aid Kit of Frogs

Imagine a frog with a cut on its skin. The frog
spends its days swimming around in a bacteriainfested
pond. Why doesn’t the cut get infected?
About 20 years ago, that question occurred
to Michael Zasloff, who is now professor in the
departments of surgery and pediatrics and the
director of surgical immunology at Georgetown
University. At the time, he was doing work with
African clawed frogs (Xenopus laevis) at the
National Institutes of Health. His curiosity led
him to discover the microbe-killing peptides
produced by specialized glands on frog skin.
Peptides are short chains of amino acids.
“When the animal is injured, it releases a
sticky gelatinous-like secretion that covers the
wound completely and protects it,” he says.
“It instantly kills any possible pathogen and
adheres to that wound for a time sufficient for
the skin to heal.”

The African clawed frog produces peptides that can be used to treat infections. (Jessie Cohen/ NZP)

Frog peptides kill bacteria by damaging their
membranes, a strategy that makes it hard for
bacteria to develop resistance. “It is extremely
difficult for a microbe to change the composition
of its membrane,” Zasloff says.

Louise Rollins-Smith, associate professor of
microbiology and immunology at Vanderbilt
University Medical Center, studies the
immune defenses of amphibians, in particular
in relation to a devastating chytrid fungus
(Batrachochytrium dendrobatidis) that is killing
frogs around the world. She describes the
frog skin secretions as a first-aid kit that may
contain painkillers, antimicrobial agents, and
antipredatory neurotoxins.

A few years ago, Rollins-Smith was discussing
her work with some Vanderbilt colleagues who
study the human immunodeficiency virus (HIV).
The scientists wondered how the frog peptides
would affect HIV. Viruses don’t have membranes,
but some—including HIV and influenza—have
“envelopes” that are similar to membranes. The
team tested several frog peptides and found
that they did kill HIV in the laboratory. “The
activity that we saw was probably disruption of
that envelope, which is required for infection,”
Rollins-Smith says. She is hopeful that the
discovery could one day lead to a topical cream
or gel that could help prevent the spread of HIV.

Several drugs based on frog peptides are
currently or soon to be in clinical trials, including
pexiganan, which is based on the peptides
Zasloff discovered in the African clawed frog.
Zasloff thinks the drug he helped create will
be on the market in the not-too-distant future.
“Without question, we will start to see over the
next few years the appearance of antimicrobial
peptides as therapeutic agents for the treatment
of infection,” he says.

A rich field of pharmacological study remains
because each of the more than 5,500 species of
frogs and toads produces several peptides, and
they are all different. Unfortunately, amphibian
populations are rapidly declining. The first-aid
kits of many frogs are being overwhelmed by
the rapidly spreading chytrid fungus. Other
amphibians are dying out due to habitat loss,
pollution, and climate change. According to
a 2004 report from the Global Amphibian
Assessment, about a third of the world’s
amphibian species are threatened, and more than
40 percent are in decline. Smithsonian National
Zoo scientists are leading efforts in amphibian
conservation—particularly with chytrid fungus
research—to help these valuable species.

From Lizard Spit to Diabetes Drug

Good poison?
The venom of the
Gila monster can do
serious harm, but
it also offers many
potential medical
applications. (Jessie Cohen)

Although rarely if ever fatal to humans, the bite
of a Gila monster (Heloderma suspectum) is an
extremely unpleasant experience. The lizard
clamps down and doesn’t let go, “chewing” to
release venom into the tissue of the victim. The
venom causes excruciating pain and a host of
other symptoms, from low blood pressure to
nausea to irregular heart rhythm. In defense of
Gila monsters, it must be said that they virtually
never bite humans unless physically provoked.

“These lizards can’t sprint like most lizards;
their top speed is a slow walk,” says Daniel
Beck, professor of biological sciences at Central
Washington University and author of Biology of
Gila Monsters and Beaded Lizards. “Their venom
is used for defense. It’s one of the most painful
venoms there is.” Gila monsters eat bird and
reptile eggs and young nestlings such as baby
cottontail rabbits. Because their prey can’t run
away, they don’t need venom to catch it.

Gila monsters, one of only two species
of venomous lizards in the world, live in the
deserts of Arizona, Utah, Nevada, New Mexico,
and Mexico, where they spend up to 95 percent
of their time resting underground.

Their venom, which is produced in modified
salivary glands, consists of about a dozen
compounds, including enzymes and peptides.
In the 1990s, John Eng of the Bronx Veterans
Administration Medical Center in New York
discovered that one of the peptides, exendin-4,
had potential as a drug to treat diabetes. The
synthetic version, called exenatide (Byetta), was
approved by the FDA in 2005.

Another component of the venom, gilatide,
is being studied as a possible memory enhancer.
Beck speculates that a memory booster in the
venom would help attackers remember to
stay away from the black-and-orange lizards
in the future.

Laboratory studies have shown the levels
of exendin-4 go up dramatically in a Gila
monster’s body while it is eating, suggesting
it may play a role in the lizard’s digestion of
large infrequent meals. “They can go a whole
year without eating at all, or they can eat ten
or 20 meals a year,” Beck says. “They tank up
when food is available and they store food very
efficiently when it is not.”

As a diabetes drug, the synthetic version
of exendin-4 works in humans in four
different ways, according to John Buse, chief
of endocrinology at the University of North
Carolina School of Medicine in Chapel Hill,
and the leader of a recent study of exenatide’s
effectiveness. “Exenatide is like a steam roller
for keeping the blood sugar from going up,” he
says. When blood sugar is too high, the drug
stimulates the production of insulin, helping
the body’s cells take up sugar to use as energy.
It also reduces a peptide called glucagon that
elevates blood sugar. And it slows emptying
of the stomach and makes people feel full fast,
causing some people to lose weight. “The total
weight loss over two years averages ten to 15
pounds,” Buse says, “but some people lose a
lot more weight.”

Years ago, when Beck was tracking Gila
monsters as a graduate student in Utah, he says
people would ask him why he was studying
these reclusive lizards instead of doing
something more useful with his career. “Now
there is this drug developed from their venom
that’s helping people with type 2 diabetes,” he
says. “It’s not necessary to justify biodiversity
based on what it can do for people, but it’s
nice to have examples of an animal that can
help save people’s lives. If we didn’t have them
around, we’d be diminished.”

Deadly Saviors

If you’re a shell collector, you’re familiar with
cone shells—marine gastropods (snails) that
live in tropical oceans around the world, mostly
in shallow waters. They are prized for the beauty
and diversity of patterns on their shells. Medical
researchers also prize cone snails, but for a
different reason—the diversity of their venom.
Cone snails (Conus spp.) use venom to subdue
their prey. About 80 percent of cone snail species
eat marine worms called polychaetes, about
ten percent eat other gastropods (including
other cone snails), and about ten percent eat
fish, according to Thomas F. Duda, Jr., assistant
professor of ecology and evolutionary biology
at the University of Michigan and a research
associate with the Smithsonian Tropical
Research Institute. “It’s probably the only
gastropod that preys on living fishes,” he says.

The cone snail's venom has compounds that can be used in pain relievers and other drugs. (Doug Perrine / naturepl.com)

When a cone snail senses prey nearby, it reaches
out its proboscis—a long skinny extension from
the mouth. If the proboscis feels suitable prey, a tiny
harpoon-like tooth shoots out of the proboscis at
200 meters per second (about 400 miles per hour),
and injects the prey with venom that paralyzes it in
milliseconds. Cone snails occasionally sting human
divers or collectors, causing pain, respiratory distress,
and sometimes death.

Cone snail venom contains peptides called
“conotoxins.” The conotoxins work by blocking
ion channels, which are pores in cell membranes.
The opening and closing of these pores control
the flow of ions across cell membranes, which in
turn control many basic cell functions.

Each species’ venom contains as many as 100 or
more different conotoxins, all of which are probably
unique to that species. With 500 to 700 species,
that makes the genus a pharmacological treasure
trove. A compound from the venom of the fisheating
cone snail Conus magus has been isolated
and synthesized as the drug ziconotide (Prialt),
approved by the FDA in 2004 for the treatment of
chronic severe pain. The drug must be administered
by a pump directly into the spinal fluid.

“We’ve really only touched the tip of the iceberg,”
says Jon-Paul Bingham, assistant professor at the
University of Hawaii at Manoa on the island of
Oahu. He says at least seven other synthetic drugs
based on conotoxins are currently undergoing
trials to treat ailments as wide-ranging as epilepsy,
incontinence, and shingles.

Scientists around the world are continuing
to look for more applications. For most
scientists, the easiest way to get venom out of
a cone snail is to kill it and dissect it. Bingham
has worked out a reliable way to raise the
snails and “milk” them for venom. “What we’re
hoping to do is establish a venom bank, which
will allow scientists all over the world to analyze
the compounds for potential pharmaceutical
application,” he says. “And we want to do it in a
biosustainable manner. You don’t kill the goose
that lays the golden egg.”

Bingham keeps 25 species of cone snails in
tanks and carefully analyzes the conditions
under which they produce the most venom, and
how the makeup of the venom varies. Unlike
snakes, scorpions, or spiders, cone snails have the
ability to modify the make-up of their venom
over several weeks, depending on the types of
prey they encounter. “We’re like dairy farmers,”
he says. “We want to make sure our cattle are
happy, well fed, producing the maximal amount
of milk they can, and we want to know if we can
get more cream by changing their diet.”

In addition to collecting venom for others,
Bingham and his students are also studying the
venom for possible drug applications. He says,
“Every time we milk, I wonder, ‘What’s in there
that may be a revolution to molecular medicine?’”
Unfortunately, some cone snail species
may be declining or even going extinct. Duda
says scientists don’t know enough about cone
snail populations or their evolutionary history
to have a picture of the overall health of the
genus, but he suspects some may be in trouble.

Cone snails are associated with coral reefs,
many of which are threatened. “Some Conus
species are restricted to very small areas,” he
says. “Some people have noted that with coastal
development, some Conus are no longer present.
We really don’t know if they are going extinct,
but we can’t afford to lose them.”